16-728534-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032304.4(HAGHL):c.428C>G(p.Ser143Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000654 in 1,376,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000065 (0 hom.)
• Consequence: HAGHL NM_032304.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0690

Genes affected

HAGHL (HGNC:14177): (hydroxyacylglutathione hydrolase like) Predicted to enable hydroxyacylglutathione hydrolase activity and metal ion binding activity. Predicted to be involved in methylglyoxal catabolic process to D-lactate via S-lactoyl-glutathione. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2438623).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HAGHL	NM_032304.4	c.428C>G	p.Ser143Trp	missense_variant	5/8	ENST00000389703.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HAGHL	ENST00000389703.8	c.428C>G	p.Ser143Trp	missense_variant	5/8	1	NM_032304.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000654 AC: 9 AN: 1376760 Hom.: 0 Cov.: 32 AF XY: 0.00000294 AC XY: 2 AN XY: 679204

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000836

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 19, 2024

The c.428C>G (p.S143W) alteration is located in exon 5 (coding exon 5) of the HAGHL gene. This alteration results from a C to G substitution at nucleotide position 428, causing the serine (S) at amino acid position 143 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Benign	-0.10
Cadd	Benign	15
Dann	Benign	0.87
DEOGEN2	Uncertain	0.56	D;.;T;.;D
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.78	T;T;T;T;T
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.24	T;T;T;T;T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	0.63	N;.;.;N;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.2	N;N;N;N;.
REVEL	Uncertain	0.45
Sift	Uncertain	0.019	D;T;T;T;.
Sift4G	Uncertain	0.020	D;D;D;D;D
Polyphen		0.023	B;.;B;B;.
Vest4		0.34
MutPred		0.63		Loss of disorder (P = 0.0036);Loss of disorder (P = 0.0036);Loss of disorder (P = 0.0036);Loss of disorder (P = 0.0036);Loss of disorder (P = 0.0036);
MVP		0.29
MPC		0.27
ClinPred		0.068	T
GERP RS		-8.5
Varity_R		0.042
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs374833821; hg19: chr16-778534;